Telomerase is expressed in almost all cancer cells, including lung cancer, but it is not expressed in most normal cells, except in a small fraction of stem cells. Telomerase activity is needed to maintain the ends of linear chromosomes that become shortened as part of pre-neoplastic progression. Shortened telomeres and high telomerase activity almost always correlate with cancer severity in the lung. Our previous results have documented that a small molecule inhibitor of telomerase, GRN163L, can effectively prevent lung cancer metastasis in experimental xenograft mouse models. We hypothesize that there may be a window of therapeutic opportunity to eliminate residual lung cancer cells in patients without adversely compromising normal stem cell function. Our long-term goal is to determine the most effective way to combine standard chemotherapy with telomerase inhibitors clinically so as to prevent or prolong the time to relapse or progression of patients with advanced lung cancer as well as prevent recurrences in early stage non-small cell lung cancer after standard surgical resection. To accomplish this goal our specific aims are as follows: Aim 1) To complete a Phase I sequential cohort, dose escalation trial to determine the safety, tolerability, and maximum tolerated dosage of weekly administered GRN163L in combination with paclitaxel and carboplatin in patients with advanced or metastatic non-small cell lung cancer. We will include correlative studies on circulating tumor cells (CTC) to determine if telomerase is inhibited and if the absolute number of CTCs decreases. Aim 2) To determine if the combination of telomerase inhibitors with additional chemotherapeutic agents results in anti-lung cancer effects in preclinical models. Aim 3) To determine if the telomerase inhibitor, GRN163L, targets the putative stem cell subpopulation of lung cancer cells.